Known Near Neighbours of Initial Tres Cantos Leads

Published by MatTodd on 28 August 2011 - 7:01am

We're starting with the resynthesis of two leads from the GSK Tres Cantos dataset. The obvious question is: are there other, related structures in the dataset that might give us information on what to change next?

 

Paul Willis from MMV did a quick "near neighbour" search (25 Aug 2011), particularly with an eye to getting rid of the ester in the lead structures. Structures below. As he said: "The first compound is a ketone analogue of the ester lineage – it's a singleton and not an ideal group from a drug discovery perspective but indicates other groups may be tolerated.  The next set is the entire cluster output of another near neighbor I spotted – all have replacements for the ester group (again not especially drug like but possible indication that wide variation possible at this position) and interestingly some contain variations on the 4-F-Ph"

 

Cc1ccc(cc1)n2c(cc(c2C)C(=O)CN3C(=O)C(NC3=O)Cc4ccccc4)C
Cc1cc(c(n1c2ccc(cc2)Cl)C)C=C3C(=O)N(C(=Nc4ccccc4)S3)C5CCCC5
Cc1ccnc(c1)n2c(cc(c2C)C=C3C(=O)N(C(=Nc4ccccc4)S3)Cc5ccco5)C
Cc1cc(cc(c1)n2c(cc(c2C)C=C3C(=O)NC(=Nc4ccc(cc4)Cl)S3)C)C
CCOC(=O)c1ccc(cc1)n2c(cc(c2C)C=C3C(=O)N(C(=Nc4ccccc4)S3)C5CCCC5)C
CCn1c(cc(c1C)C=C2C(=O)NC(=Nc3ccccc3)S2)C

 

Questions:

 

1) Are there other structures that are "similar" in the GSK set - searchable at Chembl.

2) What do these structures tell us about what to change next in the lead compounds?

3) Importantly, can we gain access to analogous structures that have been evaluated but not reported?

Interestingly this includes compounds that are related to the TC hits above but which were perhaps assayed against other targets.

Data for the above compounds will be posted to the wiki page. Discussion of them can more easily happen in comments below.

Comments

I've just started testing out a synthesis to these near neighbours (PMY 14-1). I'm going after an analogue of the compounds I already have to hand though.

MatTodd's picture

The near neighbours were to some extent included in the project, though not all of the structures included above have, to date, been included. See the overall Story so Far for the current situation. Some of these near neighbours were very insoluble, though they did show significant late stage gametocyte activity. The compounds remain of interest.